In-dwelling device related infections constitute a major cause of morbidity and mortality in hospitalized patients and add considerably to medical cost. Microbial biofilms tend to readily develop on all types of devices, urinary, endotracheal, intravenous, and implants inserted into more than 25% of patients during hospitalization. The incidence of bacterial infections in catheterized patients is approximately 5-10% per day with virtually all patients who undergo long-term catheterization (≧28 days) becoming infected.
The first stage in biofilm formation from planktonic microorganisms is adhesion to solid surfaces. Adhesion stimulates bacterial or fungal aggregation and proliferation forming micro-colonies. The colonies excrete an encasing exopolysaccharide ‘slime’ which consolidates their attachment to surfaces and the microaggregates differentiate into characteristic biofilms. Biofilm differentiation is also aided by quorum-sensing molecules which generate concentration gradient-dependent signals that control and alter the expression of a large number of genes.
The encasing extracellular polysaccharide matrix regulates the exchange of ions and nutrients between biofilms and their surrounding environment. This regulation contributes to approximately 1000 fold increase in the resistance of biofilms to antibiotics as compared with planktonic bacteria. Microbial biofilms also present serious challenges to the immune system because the expression of bacterial antigens within the encasing polysaccharide matrix is suppressed and the colony structures are highly resistant to phagocytosis. Altogether, these properties render biofilms exceedingly difficult to eradicate and explain the severity, persistence, and high levels of morbidity associated with infections produced by biofilms.
Current materials from which such medical devices are made include silicone rubber, Teflon®, polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC), polyurethane (PU), polytetrafluoroethylene (PTFE), Nylon®, polyethylene terephthalate (PET), and glass. These materials, however, lack the desired degree of slipperiness rendered by having a low coefficient of friction. It is necessary for the surface of these medical devices to have a low coefficient of friction to prevent injury, irritation, or inflammation to the patient and also to facilitate medical and surgical procedures.
Technologic innovations to prevent nosocomial infection are most likely to be most effective if they are based on a clear understanding of the pathogenesis and epidemiology of the infection. Novel technologies must be designed to block Catheter Associated Urinary Tract Infections (CAUTI) by either the extraluminal or intraluminal routes or both. Technologic innovations have been proposed and evaluated during the past 25 years but have not proven conclusively beneficial. Among these innovations are using anti-infective lubricants when inserting the catheter; soaking the catheter in an anti-infective, anti-microbial drug solution before insertion; continuously irrigating the catheterized bladder with an anti-infective solution through a triple-lumen catheter; or periodically instilling an anti-infective solution into the collection bag. Bladder irrigation with anti-microbial drug solutions has not only shown no benefit for prevention, but has been associated with a strikingly increased proportion of CAUTIs caused by microorganisms which are resistant to the drugs in the irrigating solution.
Given the widely accepted importance of closed catheter drainage, efforts have been made to seal the connection between the catheter and the collection tubing. An initial trial with a novel catheter showed a modest benefit and suggested a reduction in hospital deaths; however, follow-up studies have not demonstrated a reduction in CAUTI with a sealed catheter-collecting tube junction.
The severe and potentially fatal consequences of microbial biofilm infections have generated efforts to prevent biofilm formation, particularly on indwelling devices. Catheters coated with hydrogel, silver salts, and anti-microbials have been proposed, however they provide minimal reduction in infection incidence. A somewhat better efficacy appears to be achieved with releasable swiveling catheter securement devices.
Medicated catheters, which reduce the adherence of microorganisms to the catheter surface, may confer a greater benefit for preventing CAUTI. Two catheters which are impregnated with anti-infective solutions have been studied in randomized trials. One was impregnated with the urinary antiseptic nitrofurazone and the other with a new broad-spectrum anti-microbial drug combination, minocycline, and rifampin. Both catheters showed a significant reduction in bacterial CAUTIs; however, the studies were small, and selection of anti-microbial drug resistant uropathogens was not satisfactorily resolved.
The universal presence of a biofilm on the surface of an infected catheter has prompted hope that coating the catheter surface with an antiseptic, such as a silver compound, might reduce the risk for CAUTI. However, silver oxide-coated catheters, which had been initially reported to show promise, did not show efficacy when studied in large, well-controlled trials. In one of the trials, male patients who did not receive systemic antibiotics and had a coated catheter had a paradoxical and inexplicably increased risk for CAUTI.
Studies have shown that the addition of low-frequency ultrasound simultaneous with the application of antibiotics enhances the effectiveness of the antibiotic in killing the bacteria. In-vitro experiments to this effect were reported. It was found that when ultrasonic energy in conjunction with administration of an antibiotic (gentamicin) was applied to bacteria sequestered in a biofilm, a significantly greater fraction of the bacteria were killed than by using the antibiotic alone. Ultrasound by itself was not found to have any significant effect on the bacteria.
Similarly, it was found, that a synergistic effect was observed when ultrasound was applied in combination with gentamicin to in-vitro bacterial biofilms. These results may have application in the treatment of bacterial biofilm infections on implant devices. Ultrasound by itself was not found to be effective in inhibiting bacterial growth, except possibly at power levels high enough to cause cavitation. However, this would damage surrounding tissues in the body, as well.
Mechanical approaches to preventing biofilm formation have utilized ultrasonic energy, yet the focus has thus far been on increasing biofilm sensitivity to antibiotics. Ultrasound combinations with antibiotics were found effective only in reducing E. Coli biofilm burden in animal models, and fall short of providing a comprehensive solution to the biofilm problem.
The biofilm is formed due to intraluminal and extraluminal contamination (as shown in FIG. 1, routes of entry of uropathogens to catheterized urinary tract). Recent studies show that CAUTI most frequently stem from microorganisms gaining access extraluminally (66%) and intraluminally (34%). Extraluminal contamination may occur early, by direct inoculation when the catheter is inserted, or later, by organisms ascending from the perineum by capillary action in the thin mucous film contiguous to the external catheter surface. Intraluminal contamination occurs by reflux of microorganisms gaining access to the catheter lumen from failure of closed drainage or contamination of urine in the collection bag.
The aforementioned methods all aim to clean the medical device from contaminations and accumulated deposits, and not by fighting against the initial access of bacteria; not by pushing them out and not by preventing the first step of biofilm formation which is the adhesion of bacteria to a surface.
For example, U.S. Pat. No. 6,681,783 (Kawazoe) describes a method of cleaning a medical instrument which already has developed contamination on the inner side of the device by inserting an additional cleaning catheter with ultrasonic vibrators. (This may also be a biofilm.) A second cleaning device cleans the first one. The disadvantages of this method are:                1. The urinary or IV catheter cannot function during the cleaning procedure because the functional passageway will be used for inserting an additional cleaning catheter. This prevents the use of these types of catheters because, since they are disposable, they would not be cleaned.        2. Only the internal surface of the medical device could be cleaned with this method. This leaves the external surface (on which the most biofilm develops) without treatment.        3. As is known in the art, the ultrasound energy levels for cleaning purposes are very high which contradicts with safety requirements.        4. The device needs to be extremely small so that it may enter the channel of the catheter. Typically, the diameter of the internal channel of a urinary catheter is approximately 2 mm and the diameter of the internal channel of an IV catheter is approximately 1 mm. This prevents the use of these types of catheters. Using Kawazoe's transducer for urinary and IV catheters is therefore technically impossible.        
U.S. Pat. No. 5,271,735 (Greenfeld) proposes to solve the cleaning of catheter external surfaces by making special grooves on the catheter surface. These grooves trap contaminating debris by transmitting energy through these grooves, thus disabling the microorganisms. Disadvantages of this device include:                1. This device could not be applied to a standard medical device because it needs to create a special construction catheter.        2. The formation of biofilm is not prevented.        3. Extraluminal and intraluminal bacteria access is not prevented.        4. Due to high energy levels being used, a special medical device must be constructed because the energy levels applied for cleaning are too high for safe and continuous use. These energy levels will change the mechanical qualities of the device and leaching problems will arise.        5. The energy levels which disintegrate bacteria, will, on the other hand, damage tissue in contact with the catheter.        
U.S. Pat. No. 4,698,058 (Greenfeld) describes conveying vibrations to proximal orifices of the indwelling catheter for disintegrating accumulated deposits and contaminating bacteria in these specific places (orifices). This means that the problem is only overcome at specific places—to clean deposits on proximal orifices of the medical device. The vibration energy may be transmitted through fiber or liquid. The source of vibrations energy is a standard ultrasound transducer. Shear and compressional waves are applied. Disadvantages of this device include:                1. The transducer is a horn type which transfers the vibrations in one direction only—longitudinal. Such vibrations will push bacteria into the body, which is opposite to what is desired.        2. The beginning of the process, when the catheter is inserted into the urinary tract is a sterile system. If bacteria are prevented from entering, then the formation of a biofilm will be prevented. This will also solve the CAUTI problem.        3. Additional sensors are taught for sensing functions.        
Clinical ultrasound systems are mainly used for imaging, although there are also some therapeutic devices in use and others that have been suggested in the patent literature. For example, Talish, in International Patent Application No. PCT/US98/07531, whose disclosure is incorporated herein by reference, describes an apparatus for ultrasonic bone treatment. The apparatus includes a therapeutic ultrasonic composite comprising a transducer and an integrated circuit unit positioned adjacent thereto. In operation, the apparatus is placed against the skin adjacent to a wound area, and driving signals are transmitted to the transducer for the creation of therapeutic ultrasound in the area of the bone. Another device of this type, for promoting vascularization and epitheliazation of a wound inside the body is described in U.S. Pat. No. 5,904,659 (Duarte et al.), whose disclosure is also incorporated herein by reference.
U.S. Pat. No. 5,725,494 (Brisken), whose disclosure is incorporated herein by reference, describes an ultrasonic catheter with a resonantly-vibrating assembly at its distal end for treating vascular clot and plaque. The distal end is positioned in the area of a clot or stenosis in a blood vessel, and the vibrating assembly administers ultrasonic energy to break up the clot or other stenotic lesions. The catheter may also be used in conjunction with a therapeutic agent.
U.S. Pat. No. 7,014,627 (Bierman), whose disclosure is incorporated herein by reference, deals with catheter securement system, and describes and claims the specific construction for catheter securement to the patient's body. Another relevant patent is U.S. Pat. No. 4,397,647 (Gordon), whose disclosure is incorporated herein by reference, which deals with constructions of catheter securement systems. Neither of these references contains active elements in the securement system like the one proposed in the invention.
A welcome addition to the art would be a medical device having the ability to prevent biofilm formation on surface areas of devices, as well as methods of increasing a level of such prevention in other medical devices.